PROJECT SUMMARY CLINICAL RESEARCH PROJECT The goal of the Clinical Project is to generate and integrate a complex network of clinical, immunologic, metabolic, and microbiome datatypes on the ME/CFS etiology to engender hypotheses on immune dysfunction in ME/CFS disease mechanisms. Given the lack of diagnostic molecular markers for ME/CFS and a very limited understanding of its etiology, there is critical need to define new risk factors and mechanisms of ME/CFS predisposition and severity. While early studies showed promise in identifying different metabolic, immunologic, or microbial biomarkers of ME/CFS, these studies were limited in scope, sample size, or, importantly, integration across datatypes, examining one or a small handful of correlates at a time. While this may be sufficient for diseases with a more straightforward mechanism, ME/CFS' compound symptoms and potential etiologies require integrated analysis that incorporates multiple datatypes. In addition, longitudinal and prospective studies are needed to identify mechanisms of disease progression and severity. We hypothesize that immune dysfunction is a central etiology of ME/CFS, both by virtue of its propensity to respond aberrantly to environmental stimuli and its vulnerability to aberrant stimulation by the ME/CFS microbiome and/or its metabolites. Our goal is to define likely clinical correlates of ME/CFS disease, centering on the microbiome and metabolome as immune triggers. We will address multiple central goals of the Center, most notably the application of computational modeling and machine learning approaches to integrate detailed clinical, immune, metabolomic and microbiome datatypes to characterize and predict the immune responses triggered and the associated clinical correlates. Moreover, this study will provide, in addition to valuable hypotheses to guide the mechanistic work proposed in the Basic Research Project, a battery of different immune, metabolomic, and microbial biomarkers associated with different ME/CFS subtypes and disease severity. This project benefits from the deep clinical research expertise at Bateman Horne Center and University of Utah CTSA, cutting-edge core services at The Jackson Laboratory, and the world-class computational and biostatistics team assembled here, with expertise in clinical study design and integrative modeling of large-scale complex genomics cohorts. Our Specific Aims are: 1) To assess immunological abnormalities and blood metabolomic changes prospectively in a large ME/CFS patient cohort; 2) To define correlations between microbiome ecological distribution and clinical state of ME/CFS; and 3) to establish ME/CFS clinical ontology with computational and biostatistical analysis of the immune, metabolic and microbiome interactome in ME/CFS patients. Impact: Success of our aims will yield a large-scale data repository and integrated analytic workflow that can accommodate samples from multiple centers. Identified correlates will be strong candidates for mechanistic biomarkers of disease and will provide hypotheses for mechanistic follow-up studies linking the microbiome to immune and metabolic dysbiosis in ME/CFS.